A General Catalyst Controlled Route to Prostaglandin F2α

We report a general, catalyst-controlled route to prostaglandin F2α and its analogues. The approach uses a Rh-catalyzed dynamic kinetic asymmetric Suzuki–Miyaura coupling reaction between a racemic bicyclic allyl chloride and alkenyl boronic esters bearing chiral alcohols to give cyclopentyl intermediates bearing 3 contiguous stereocenters. The route provides advanced intermediates in 99% ee as a single diastereoisomer in all cases examined, with the absolute stereochemistry of the cyclopentane core controlled by the ligand. Intermediates that could be used to produce prostaglandin analogues such as bimatoprost, latanoprost, fluprostenol, and cloprostenol were synthesized. The final two stereocenters were installed via Pd-catalyzed Tsuji–Trost alkylation and iodolactonization. The synthesis of PG F2α was achieved in 19% yield in 16 longest linear steps.


General procedure D: Desilylation of alkyne
To a solution of alcohol (1 equiv) in THF (0.1 M) was added TBAF (1.2 equiv, 1.0 M in THF) at RT. After stirring for 1 h, the reaction was quenched with sat. aq. NH4Cl and the aqueous layer was extracted with Et2O. The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The resulting alcohol was used without further purification.
Alkyne S2a was prepared according to general procedure D from TIPS protected 3a (56 mmol) and was used without further purification. Alkyne S2f was prepared according to general procedure D from TIPS protected 3f (9 mmol) and used without further purification.

General procedure E: TBS protection of alcohol
Alcohol (1 equiv) was dissolved in DCM (1 M) along with DMAP (5 mol%) and imidazole (1.5 equiv) at 0 ˚C. TBS chloride was added and the resulting suspension was warmed to RT and stirred for one hour. The mixture was diluted with DCM and washed with sat. aq. NH4Cl. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. Purification by column chromatography yields the desired product.

General procedure F: Borylation of alkyne
To a flame tried high pressure flask was added 4-methylaminobenzoic acid (5 mol%) and pinacolborane (3 equiv) under an inert atmosphere. A solution of alkyne (1 equiv) in dry heptane (1 M) was added, and the flask was sealed then heated to 110 ˚C using an oil bath for 16h. The flask was cooled, and the mixture was diluted with EtOAc and washed with NH4Cl. The aqueous layer was separated and extracted with EtOAc, and the combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The resulting oil was purified by column chromatography to yield the boronic ester.
After flask A stirred for 30 min, the contents of flask B were added via syringe, and flask B was washed with 0.3 mL THF which was also added to flask A. Reaction progress was monitored by 1 H NMR spectroscopy. Upon completion (1-3 h), silica gel was added directly to the reaction mixture which was concentrated and dry loaded for purification by silica gel chromatography.
Note: For compound 6, no change was made to the experimental procedure when increasing scale to 5 mmol of allyl chloride other than the size of the flasks usedall other factors (time, temperature etc.) were consistent with the procedure used for reactions carried out on a 0.5 mmol scale. Flask A size used is 25 mL, and flask B size is 50 mL..